Modulation of prostaglandin metabolism is at the centre of current anti-inflammatory therapies. NSAIDs and COX-2 inhibitors block the activity of cyclooxygenases and their ability to convert arachidonic acid into prostaglandin H2 (PGH2). PGH2 can be subsequently metabolized by terminal prostaglandin synthases to the corresponding biologically active PGs, namely, PGI2, thromboxane (Tx) A2, PGD2, PGF2a and PGE2. A combination of pharmacological, genetic and neutralizing antibody approaches demonstrates the importance of PGE2 in inflammation. The conversion of PGH2 to PGE2 by prostaglandin E synthases (PGES) may therefore represent a pivotal step in the propagation of inflammatory stimuli.
Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible PGES after exposure to pro-inflammatory stimuli. mPGES-1 is induced in the periphery and in the CNS by inflammation and represents therefore a target for acute and chronic inflammatory disorders.
PGE2 is a major prostanoid driving inflammatory processes. The prostanoid is produced from arachidonic acid liberated by Phospholipases (PLAs). Arachidonic acid is transformed by the action of Prostaglandin H Synthase (PGH Synthase, cyclooxygenase) into PGH2, which is a substrate for mPGES-1, which is the terminal enzyme transforming PGH2 to the pro-inflammatory PGE2.
NSAIDs reduce PGE2 by inhibiting cyclooxygenase, but at the same time reducing other prostanoids, giving side effects such as ulcerations in the GI tract. mPGES-1 inhibition gives a similar effect on PGE2 production without affecting the formation of other prostanoids, and hence a more favourable profile.
By blocking the formation of PGE2 in animal models of inflammatory pain a reduced inflammation, pain and fever response has been demonstrated (see e.g. Kojima et. al, The Journal of Immunology 2008, 180(12): 8361-8368; Xu et al., The Journal of Pharmacology and Experimental Therapeutics 2008, 326(3): 754-763).
Osteoarthritis is an inflammation of one or more joints, caused by the loss of cartilage leading to loss of water, while rheumatoid arthritis is considered to be of autoimmune origin. In several models of arthritis, inhibition of mPGES-1 leads to a reduced inflammation and/or pain (Kojima et al., Fundamental & Clinical Pharmacology 2005, 19(3): 255-261).
In abdominal aortic aneurism, inflammation leads to connective tissue degradation and smooth muscle apoptosis ultimately leading to aortic dilation and rupture. In animals lacking mPGES-1 a slower disease progression and disease severity has been demonstrated (see e.g. Wang et al., Circulation 2008, 117(10): 1302-1309).
Several lines of evidence indicate that PGE2 is involved in malignant growth. PGE2 facilitates tumor progression of many different types of cancers, by stimulation of cellular proliferation and angiogenesis and by modulation of immunosuppression (see e.g. Menter et al., International Journal of Cell Biology 2012; Nakanishi et al., Biochimie 2010, 92(6): 660-664; Kamata et al., Biomedicine & Pharmacotherapy 2010, 64(6): 409-416; Beales et al., Int. J. Cancer 2010, 126(9): 2247-2255). In support of a role for PGE2 in carcinogenesis, genetic deletion of mPGES-1 in mice suppresses the intestinal tumourogenesis (Nakanishi et al., Cancer Research 2008, 68(9): 3251-3259), hepatocarcinogenesis (Lu et al., Oncogene 2012, 31(7): 842-857) and bone cancer (Isono et al., Life Sciences 2011, 88(15-16): 693-700). In man, mPGES-1 is also upregulated in cancers such as colorectal cancer (see e.g. Schröder et al., Journal of Lipid Research 2006, 47(5): 1071-80) and non-small-cell lung cancer (NSCLS) (Wang et al., Annals of Surgical Oncology 2006, 13(9): 1224-1234).
Myositis is chronic muscle disorder characterized by muscle weakness and fatigue.
Proinflammatory cytokines and prostanoids have been implicated in the development of myositis. In skeletal muscle tissue from patients suffering from myositis, an increase in cyclooxygenases and mPGES-1 has been demonstrated, implicating mPGES-1 as a target for treating this condition (see e.g. Korotkova et al., Annals of the Rheumatic Diseases 2008, 67(11): 1596-1602).
In atherosclerosis, inflammation of the vasculature leads to atheroma formation that eventually may progress into infarction. In patients with carotid atherosclerosis, an increase in mPGES-1 in plaque regions has been found (Gómez-Hernández et al., Atherosclerosis 2006, 187(1): 139-149). In an animal model of atherosclerosis, mice lacking the mPGES-1 receptor were found to show a retarded atherogenesis and a concomitant reduction in macrophage-derived foam cells together with an increase in vascular smooth muscle cells (see e.g. Wang et al., Proceedings of National Academy of Sciences 2006, 103(39): 14507-14512) and reduced neointimal hyperplasia (Wang et al. Circulation 2011, 123(6): 631-639).
PGE-2, produced via mPGES-1, exerts a control of apnea frequency and mPGES-1 KO mice show reduced sensitivity to IL-1 induced anoxia (Hofstetter et al., Proceedings of National Academy of Sciences 2007, 104(23), 9894-9899).
Inflammation is part of the Alzheimer pathology, and mPGES-1 levels are higher in neuronal tissue from AD patients (Chaudhry et al., Alzheimer's & Dementia 2008, 4(1): 6-13).
Bis(sulfonamide) compounds which are useful for the treatment of pain and inflammatory diseases have been suggested in WO2007/042817, WO2008/129276, WO2008/129288, WO2009/064250, WO2009/064251, WO2009/082347 and WO2010/132016.
There is still a need for compounds that have an improved potency and improved selectivity to PGE2. There is a need for compounds having reduced side effect, such as gastrointestinal and renal toxicity.